* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Gene Section EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)
Cell-penetrating peptide wikipedia , lookup
G protein–coupled receptor wikipedia , lookup
Histone acetylation and deacetylation wikipedia , lookup
Messenger RNA wikipedia , lookup
Magnesium transporter wikipedia , lookup
Transcriptional regulation wikipedia , lookup
Protein structure prediction wikipedia , lookup
Interactome wikipedia , lookup
Protein (nutrient) wikipedia , lookup
Epitranscriptome wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Protein moonlighting wikipedia , lookup
Secreted frizzled-related protein 1 wikipedia , lookup
Western blot wikipedia , lookup
Gene regulatory network wikipedia , lookup
Nuclear magnetic resonance spectroscopy of proteins wikipedia , lookup
Silencer (genetics) wikipedia , lookup
Paracrine signalling wikipedia , lookup
Protein adsorption wikipedia , lookup
Expression vector wikipedia , lookup
Protein–protein interaction wikipedia , lookup
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1) Michael Clemens, Mark Coldwell Dept. of Chemistry and Biochemistry, School of Life Sciences, University of Sussex and Division of Basic Medical Sciences, St George's, University of London, United Kingdom (MC), School of Biological Sciences, University of Southampton, United Kingdom (MC) Published in Atlas Database: February 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/EIF4EBP1ID40432ch8p12.html DOI: 10.4267/2042/44655 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Pseudogene Other names: BP-1; 4EBP1; 4E-BP1; PHAS-I; MGC4316 HGNC (Hugo): EIF4EBP1 Location : 8p12 Two pseudogenes with homology to 4E-BP1 exist in the human genome, located at 14q11.2 (LOC768328) and 22q12 (EIF4EBP1P), with the latter pseudogene present on the antisense strand of the gene locus encoding chromodomain helicase DNA binding protein 8 (CHD8). DNA/RNA Protein Description Description The EIF4EBP1 gene codes for 4E-BP1, one member of a family of small proteins that act as repressors of translation. The gene is 29.86 Kb in length and contains three exons, comprising nucleo-tides 1-217, 218-397 and 398-859 of the mature mRNA. Human 4E-BP1 is a 118 amino acid protein (119 amino acids including the initiating methionine) and is encoded by an mRNA containing 877 nucleotides (including a short poly(A) tail). The mRNA has a 72 nucleotide 5' untranslated region and a 448 nucleotide 3' untranslated region. The coding region comprises nucleotides 73-429. The protein can be reversibly phosphorylated at Thr37, Thr46, Ser65, Thr70, Ser83, Ser101 and Ser112 in response to a variety of physiological stimuli. Transcription Activity of the promoter of the EIF4EBP1 gene is regulated by the Forkhead-O1 (FOXO1) transcript-tion factor (Southgate et al., 2007). Over-expression of FOXO1 enhances the levels of 4E-BP1 mRNA and protein. The consequent accumulation of the hypophosphorylated form of 4E-BP1 impairs overall protein synthesis. There is evidence that activity of the phosphatidylinositol 3-kinase (PI3K) and MAP kinase pathways can negatively regulate the transcription of EIF4EBP1 (Azar et al., 2008), possibly via the transcription factor Egr-1 (Rolli-Derkinderen et al., 2003). Conversely, EIF4EBP1 transcription is positively regulated by ATF4 in response to cell stress (Yamaguchi et al., 2008). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1) Expression 4E-BP1 is ubiquitously expressed, although its presence is not essential to the viability of cells or the organism as a whole (Le Bacquer et al., 2007). The level of expression and state of phospho-rylation of the protein may influence cellular phenotype, with high levels of phosphorylated 4E-BP1 in breast, ovary, and prostate tumours being associated with malignant progression and an adverse prognosis (Armengol et al., 2007). 11 EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1) Clemens M, Coldwell M The diagram illustrates key regulatory features of the human 4E-BP1 protein, including the RAIP and TOS motifs that are important for the phosphorylation of the protein at Thr37, Thr46, Ser65, Thr70 and Ser101 by the Raptor/mTOR complex (Eguchi et al., 2006; Lee et al., 2008). Additional phosphorylation sites have been identified at Ser83 and Ser112. The region required for binding of 4E-BP1 to initiation factor eIF4E and a site of cleavage of the protein by caspases in apoptotic cells are also shown. (Diagram adapted from an original prepared by Dr C. Constantinou). Conver-sely, hypophosphorylated 4E-BP1 may have an anti-oncogenic role due to its inhibitory effect on eIF4E. or activation of the tumour suppressor protein p53 (Tilleray et al., 2006; Constantinou and Clemens, 2007) - cause dephosphorylation of 4E-BP1 and increase binding of the latter to eIF4E. 4E-BP1 is also susceptible to other post-translational modifications, notably specific proteolytic cleavages (Tee and Proud, 2002; Constantinou et al., 2008) and phosphorylationdependent ubiqui-tination (Elia et al., 2008). Although 4E-BP1 is not essential to viability the protein (together with its homologue 4E-BP2) is important for regulation of adipogenesis and insulin resistance (Le Bacquer et al., 2007). The 4E-BPs have also been reported to play a role in myelopoiesis (Olson et al., 2008). There is a major role for 4E-BP1 in the responses of cells to hypoxia, which promotes dephosphorylation of the protein (Koritzinsky et al., 2006; Connolly et al., 2006). It is likely that this response implements hypoxiainduced changes in gene expression at the translational level (Magagnin et al., 2008; Barnhart et al., 2008). Localisation 4E-BP1 is present in both cytoplasm and nucleus. The hypophosphorylated protein in the latter compartment can sequester eIF4E within the nucleus under conditions of physiological stress (Rong et al., 2008). Function The members of the 4E-BP family of proteins act by binding to the mRNA cap-binding protein eukaryotic initiation factor 4E (eIF4E), in compe-tition with another initiation factor, eIF4G, that is essential for polypeptide chain initiation. Thus the availability of eIF4E for translation of cap-dependent mRNAs is limited by the extent to which this factor is sequestered by the 4E-BPs. 4E-BP1 is reversibly phosphorylated at multiple sites (see diagram above), in response to several physiological signals that promote translation (Proud, 2004; Wang et al., 2005; Proud, 2006). Such phosphorylations lower the affinity of 4E-BP1 for eIF4E and result in the dissociation of the two proteins, thereby enhancing the level of active eIF4E and promoting the translation of capped mRNAs, most likely in a selective manner (Averous et al., 2008). Conversely, physiological stresses and other conditions that inhibit translation - e.g. exposure of cells to cytokines of the TNFalpha family (Lang et al., 2007; Jeffrey et al., 2006) Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1) Homology 4E-BP1 was identified alongside another member of the eIF4E-binding protein family designated 4E-BP2 (Pause et al., 1994). A further homologue has also been identified, 4E-BP3 (Poulin et al., 1998), and these proteins respectively share 55.7% identity (82.0% similarity) and 50.8% identity (66.9% similarity) with 4E-BP1. All share the central eIF4E binding motif and are capable of competing with the eIF4G proteins for binding to eIF4E. 12 EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1) Clemens M, Coldwell M CLUSTAL 2.0.10 multiple sequence alignment: 4E-BP1 4E-BP2 4E-BP3 MSGGSSCSQTP--SRAIPATRRVVLGDGVQLPPGDYSTTPGGTLFSTTPGGTRIIYDRKF 58 MSSSAGSGHQPSQSRAIPT-RTVAISDAAQLP-HDYCTTPGGTLFSTTPGGTRIIYDRKF 58 MSTST--------SCPIP-------GGRDQLP-DCYSTTPGGTLYATTPGGTRIIYDRKF 44 ** .: * .** .. *** *.*******::************** 4E-BP1 4E-BP2 4E-BP3 LMECRNSPVTKTPPRDLPTIPGVTSPSS--DEPPMEASQSHLRNSPEDKRAGGEESQFEM 116 LLDRRNSPMAQTPPCHLPNIPGVTSPGTLIEDSKVEVNNLNNLNNHDRKHAVGDDAQFEM 118 LLECKNSPIARTPPCCLPQIPGVTTP------PTAPLSKLEELKEQETEEEIPDDAQFEM 98 *:: :***:::*** ** *****:* . .: . :. : :. :::**** 4E-BP1 4E-BP2 4E-BP3 DI 118 DI 120 DI 100 ** Mutations References Note No mutations have been identified. Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC Jr, Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature. 1994 Oct 27;371(6500):762-7 Implicated in Poulin F, Gingras AC, Olsen H, Chevalier S, Sonenberg N. 4EBP3, a new member of the eukaryotic initiation factor 4Ebinding protein family. J Biol Chem. 1998 May 29;273(22):14002-7 Breast cancer Prognosis Elevated expression of eIF4E in human cancer often correlates with poor prognosis (Culjkovic et al., 2007). Likewise, expression of phosphorylated 4E-BP1 (which is inactive as an inhibitor of eIF4E) is associated with malignant progression and an adverse prognosis in breast, ovary, and prostate tumours (Armengol et al., 2007). Oncogenesis Because 4E-BP1 is an antagonist of the oncogenic initiation factor eIF4E (Avdulov et al., 2004), it might be anticipated that 4E-BP1 could function as a proapoptotic tumour suppressor protein. However it has been reported that a majority of large advanced breast cancers overexpress 4E-BP1 (Braunstein et al., 2007). The latter may contribute to tumourigenesis (in combination with over-expressed eIF4G) by promoting a hypoxia-activated switch in selective mRNA translation that enhances angiogenesis and tumour cell growth and survival. Tee AR, Proud CG. Caspase cleavage of initiation factor 4Ebinding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif. Mol Cell Biol. 2002 Mar;22(6):1674-83 Rolli-Derkinderen M, Machavoine F, Baraban JM, Grolleau A, Beretta L, Dy M. ERK and p38 inhibit the expression of 4E-BP1 repressor of translation through induction of Egr-1. J Biol Chem. 2003 May 23;278(21):18859-67 Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman DM, Manivel JC, Sonenberg N, Yee D, Bitterman PB, Polunovsky VA. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell. 2004 Jun;5(6):553-63 Proud CG. mTOR-mediated regulation of translation factors by amino acids. Biochem Biophys Res Commun. 2004 Jan 9;313(2):429-36 Gelsi-Boyer V, Orsetti B, Cervera N, Finetti P, Sircoulomb F, Rougé C, Lasorsa L, Letessier A, Ginestier C, Monville F, Esteyriès S, Adélaïde J, Esterni B, Henry C, Ethier SP, Bibeau F, Mozziconacci MJ, Charafe-Jauffret E, Jacquemier J, Bertucci F, Birnbaum D, Theillet C, Chaffanet M. Comprehensive profiling of 8p11-12 amplification in breast cancer. Mol Cancer Res. 2005 Dec;3(12):655-67 Breakpoints Wang X, Beugnet A, Murakami M, Yamanaka S, Proud CG. Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Mol Cell Biol. 2005 Apr;25(7):255872 Note Although no breakpoints within the 4E-BP1 gene locus have been identified, the chromosomal region containing 4E-BP1 (8p11-12) is frequently rear-ranged in breast carcinomas. However, microarray profiling of the genes within these regions in breast tumours and cell lines shows that rearrangements of the chromosome do not correlate with significantly changed 4E-BP1 mRNA expression (Gelsi-Boyer et al., 2005). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1) Connolly E, Braunstein S, Formenti S, Schneider RJ. Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells. Mol Cell Biol. 2006 May;26(10):3955-65 13 EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1) Eguchi S, Tokunaga C, Hidayat S, Oshiro N, Yoshino K, Kikkawa U, Yonezawa K. Different roles for the TOS and RAIP motifs of the translational regulator protein 4E-BP1 in the association with raptor and phosphorylation by mTOR in the regulation of cell size. Genes Cells. 2006 Jul;11(7):757-66 Clemens M, Coldwell M mTOR signaling in mammalian skeletal muscle. J Biol Chem. 2007 Jul 20;282(29):21176-86 Averous J, Fonseca BD, Proud CG. Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene. 2008 Feb 14;27(8):1106-13 Jeffrey IW, Elia A, Bornes S, Tilleray VJ, Gengatharan K, Clemens MJ. Interferon-alpha induces sensitization of cells to inhibition of protein synthesis by tumour necrosis factor-related apoptosis-inducing ligand. FEBS J. 2006 Aug;273(16):3698708 Azar R, Najib S, Lahlou H, Susini C, Pyronnet S. Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1. Cell Mol Life Sci. 2008 Oct;65(19):3110-7 Koritzinsky M, Magagnin MG, van den Beucken T, Seigneuric R, Savelkouls K, Dostie J, Pyronnet S, Kaufman RJ, Weppler SA, Voncken JW, Lambin P, Koumenis C, Sonenberg N, Wouters BG. Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J. 2006 Mar 8;25(5):1114-25 Barnhart BC, Lam JC, Young RM, Houghton PJ, Keith B, Simon MC. Effects of 4E-BP1 expression on hypoxic cell cycle inhibition and tumor cell proliferation and survival. Cancer Biol Ther. 2008 Sep;7(9):1441-9 Constantinou C, Elia A, Clemens MJ. Activation of p53 stimulates proteasome-dependent truncation of eIF4E-binding protein 1 (4E-BP1). Biol Cell. 2008 May;100(5):279-89 Proud CG. Regulation of protein synthesis by insulin. Biochem Soc Trans. 2006 Apr;34(Pt 2):213-6 Tilleray V, Constantinou C, Clemens MJ. Regulation of protein synthesis by inducible wild-type p53 in human lung carcinoma cells. FEBS Lett. 2006 Mar 20;580(7):1766-70 Elia A, Constantinou C, Clemens MJ. Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1. Oncogene. 2008 Jan 31;27(6):811-22 Armengol G, Rojo F, Castellví J, Iglesias C, Cuatrecasas M, Pons B, Baselga J, Ramón y Cajal S. 4E-binding protein 1: a key molecular "funnel factor" in human cancer with clinical implications. Cancer Res. 2007 Aug 15;67(16):7551-5 Lee VH, Healy T, Fonseca BD, Hayashi A, Proud CG. Analysis of the regulatory motifs in eukaryotic initiation factor 4E-binding protein 1. FEBS J. 2008 May;275(9):2185-99 Braunstein S, Karpisheva K, Pola C, Goldberg J, Hochman T, Yee H, Cangiarella J, Arju R, Formenti SC, Schneider RJ. A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. Mol Cell. 2007 Nov 9;28(3):501-12 Magagnin MG, van den Beucken T, Sergeant K, Lambin P, Koritzinsky M, Devreese B, Wouters BG. The mTOR target 4EBP1 contributes to differential protein expression during normoxia and hypoxia through changes in mRNA translation efficiency. Proteomics. 2008 Mar;8(5):1019-28 Constantinou C, Clemens MJ. Regulation of translation factors eIF4GI and 4E-BP1 during recovery of protein synthesis from inhibition by p53. Cell Death Differ. 2007 Mar;14(3):576-85 Rong L, Livingstone M, Sukarieh R, Petroulakis E, Gingras AC, Crosby K, Smith B, Polakiewicz RD, Pelletier J, Ferraiuolo MA, Sonenberg N. Control of eIF4E cellular localization by eIF4Ebinding proteins, 4E-BPs. RNA. 2008 Jul;14(7):1318-27 Culjkovic B, Topisirovic I, Borden KL. Controlling gene expression through RNA regulons: the role of the eukaryotic translation initiation factor eIF4E. Cell Cycle. 2007 Jan 1;6(1):65-9 Yamaguchi S, Ishihara H, Yamada T, Tamura A, Usui M, Tominaga R, Munakata Y, Satake C, Katagiri H, Tashiro F, Aburatani H, Tsukiyama-Kohara K, Miyazaki J, Sonenberg N, Oka Y. ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress. Cell Metab. 2008 Mar;7(3):269-76 Lang CH, Frost RA, Vary TC. Regulation of muscle protein synthesis during sepsis and inflammation. Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E453-9 Olson KE, Booth GC, Poulin F, Sonenberg N, Beretta L. Impaired myelopoiesis in mice lacking the repressors of translation initiation, 4E-BP1 and 4E-BP2. Immunology. 2009 Sep;128(1 Suppl):e376-84 Le Bacquer O, Petroulakis E, Paglialunga S, Poulin F, Richard D, Cianflone K, Sonenberg N. Elevated sensitivity to dietinduced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J Clin Invest. 2007 Feb;117(2):387-96 This article should be referenced as such: Southgate RJ, Neill B, Prelovsek O, El-Osta A, Kamei Y, Miura S, Ezaki O, McLoughlin TJ, Zhang W, Unterman TG, Febbraio MA. FOXO1 regulates the expression of 4E-BP1 and inhibits Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1) Clemens M, Coldwell M. EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1):11-14. 14